Antibiotic compositions comprising erythromycin and neomycin



United States Patent O fifice 2,801,952 Patented Aug.;6, .1957

ANTIBIOTIC COMPOSITIONS COMPRISING ERYTHROMYCIN AND NEOMYCIN Robert E. Himeliclr, Kalamazoo Township, Kalamazoo County, Mich., assignor to The Upjolm- Company, Kalamazoo, Mich, a corporation of Michigan No Drawing. Application July 21, 1954,

Serial No. 444,904 a 4 Claims. (Cl. 167-65) This invention relates to antibiotic compositions, and more particularly relates to antibiotic compositions containing the two essential active ingredients, erythromycin and neomycin.

Due to the successful treatment of infectious diseases with anitibiotic materials a considerable portion of the research effort in the medical art has been devoted to the search for new and better antibiotics. Due to the development of strains of organisms resistant to existing antibiotics. the development of patient sensitivity to exisiting antibiotics, and the desire for ever improved antibiotics, continuous research is and will be carried out in the never ending struggle against infectious diseases. In recent years an increasing amount of attention has beenjgiven to the development of antibiotic combinations which possess advantages not possessed by the individual members of the combination.

It is therefore an object of the present invention to provide a novel combination of antibiotics useful in combating infectious diseases. Another object of the pressame sense as in those references and includes the therapeutically active, non-toxic salts and esters of both forms- Prior to the present invention these antibiotics have never been combined. However considerable clinical and animal tests conducted with the combination have demonstrated the efllcacy and unexpected properties thereof. Since neomycin is primarily regarded as a topical medicament, the combination is also most useful. in that form. For topical use in humans erythromycin-neomycin combinations are generally prepared in an ointment or lotion base such as those commonly known to the art. A powder base is also feasible for topical use. For animal use, such as bovine mastitis an ointment base is used with due regard to the special problems of administering such materials in the special conditions there involved.

7 Such a base is more fully described in copending application Serial No. 444,641, filed July 20, 1954. The combination also is useful when prepared in a form suitable for oral administration, such as a tablet or in a conventional liquid oral vehicle.

The following examples are merely illustrative of the compositions of the present invention and are not to be construed as limiting.

EXAMPLE l.-'IN VITRO USE In vitro, tests substantiate the synergistic effectiveness of the combination over the individual materials. The following table indicates the effect of erythromycin and neomycin alone and in combination against two of the.

The efl'ect of erythromycin and neomycin alone and in combination against certain organisms involved in bovine mastitis, in vitro Single Antibiotics MIC, Combination Studies, .MIC, meg/ml.

meg/ml. Ratio of Antibiotics in Combinations Organism Mpyoaenea vanaureua .19 12 .09 .17 .075 .09 .010 .67 Streptococcus dysgalactiae .005 .02 6.0 26 .002 .005 .0045 .0045 .002 .004 i .002 .005 .0002 .0005 .018 .036

entinvention is to provide a combination of erythromycin and neomycin which possesses advantages unattainable from either alone. Still another object is to provide a combination of antibiotics which is highly effective in the treatment of a variety of cutaneous bacterial infections. Still another object of the present invention is to provide a novel combination of antibiotics which is especially eifective in the treatment of bovine mastitis. Other objects will be apparent to one skilled in the art to which this invention pertains.

Neomycin is one of the newer antibiotics which has been fully described in Waksman in his recent work Neomycin, Rutgers University Press, 1953. The word neomycin is used here in the same sense as it is used in that work and includes the various forms of neomycin (such as the B and C forms) and its active derivatives (such as the sulfate salt).

Erythromycin is an even newer antibiotic more fully described in one form in U. S. Patent No. 2,653,899, and in another form in Pettinga et al., I. A. C. S., 76: 569-571 (1954). The word erythromycin is used here in the Moreover the overall effectiveness of the combination against all of the organisms commonly found in bovine mastitis establishes the efiicacy of the combination in those situations in which a veterinarian or doctor has no time to determine the major causative organism in a particular case of bovine mastitis. It is possible to use less of the materials in combination to inhibit all of the organisms than either antibiotic alone. Among the more common organisms found in bovine mastitis are the following: Pseudomonas aernginosa, Aerobacter aerogenes, M. pyogenes var. aurens, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, and Corynebacteriwm pyogenes. Using the method outlined in the table, the minimum inhibitory concentration of erythromycin alone for the whole group of organisms is micrograms per milliliter after 24 hours incubation; the minimum for neomycin alone is 25 micrograms per milliliter after 24 hours incubation. Using the combination of erythromycin and neomycin in a one to one ratio, only twelve micrograms per milliliter of each of the two antibiotics is required. When the ratio of erythromycin to neomycin is one to nine, only 1.2 micrograms per milliliter of erythromycin and eleven micrograms per milliliter of neomycin are required. From a practical standpoint the synergism of the combination as expressed in this way is more important than the synergism of the combination against particular organisms as sociated with the disease.

EXAMPLE 2.--CLINICAL USE Using conventional pharmaceutical techniques one-half ounce tubes of the following kinds and amounts of materials were prepared:

Erythromycin milligrams 5.0 Neomycin sulfate do 5.0 Liquid petrolatum, U. S. P. XIV "grams" 0.25 Methylparaben, U. S. P. XIV "milligrams" 0.2 n-Butyl-p-hydroxybenzoate do 1.8 Cholesterol, U. S. P. XIV do 5.0 Microcrystalline wax .do. 40.0

White petrolatum, U. S. P. XIV, q. s.

1 Sufiicient to make up one-half ounce.

The formulation containing the essential active ingredients as given above was tested in a large group of patients by several investigators and the results of these investigations were all favorable. They were used in a variety of cutaneous bacterial infections and produced prompt responses in impetigo, impetiginous dermatitis, folliculitis, paronychia, external otitis, cellulitis and secondarily infected eczema, burns an ulcers. In some cases of bacterial eczematous dermatitis that failed to improve significantly with other antibiotic preparations, this combination produced prompt clearing of the infection. Although neither of the individual antibiotics has been shown to have antifungal activity, the combination is capable of clearing lesions caused by secondary bacterial invaders even in situations where the primary causative organism is fungal in nature. One investigator used the combination in the treatment of pyodermas in nearly 200 patients. A partial report of his results can be found in Livingood et al., J. A. M. A. 153, 1266 (December 5, 1953). Another investigator treated about 150 cases of pyodermas with excellent results and no evidence of irritation and/ or sensitization. Still another investigator used the combination on a considerable number of pati ents and reported that he had not observed a single case where there was an untoward reaction to treatment and indicated that it was his belief that the overall response was much faster than with any other antibiotic used since the days of penicillin.

EXAMPLE 3.-POWDER PREPARATION A powder preparation of the composition of the present invention is prepared by conventional techniques. Each gram of such a preparation contains the following:

Mg. Neomycin sulfate powder 6 Erythromycin 6 n-Butyl-p-hydroxybenzoate 1.8 Methylparaben, U. S. P -1 0.2

Lactose 986 EXAMPLE 4.ORAL TABLETS Using conventional pharmaceutical techniques an oral dosage form containing the following ingredients can also be prepared.

Each tablet contains:

Neomycin mg 250 Erythromycin ..mg 50 Starch grains- 15 5 Sucrose do .055 Light mineral oil do .037 Calcium stearate do .04 Guar gum do .05

Starch, sucrose, and guar gum are used for granulation; the guar gum primarily for disintegration. The calcium stearate and mineral oil are used for lubricants.

The tablet can be enteric coated to protect the erythromycin by the use of a conventional enteric coating material, such as cellulose acetate phthalate.

It is to be understood that the invention is not to be limited to the exact details of operation or exact com positions shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

I claim:

1. A therapeutic composition comprising erythromycin and neomycin.

2. A therapeutic composition comprising as one essential active ingredient erythromycin, as a second essential active ingredient neomycin, and an ointment base.

3. A therapeutic composition comprising erythromycin as one essential active ingredient, neomycin as a second essential active ingredient, and a water and milk miscible vehicle.

4. A therapeutic composition comprising erythromycin, neomycin sulfate, and an ointment base.

Sulfonam., Singly and in Combination Antibiotics and Chemotherapy, July 1953, pp. 721-730.

Modern Drugs, March 1954, p. 813, Erythro- Myciguent. 

1. A THERAPEUTIC COMPOSITION COMPRISING ERYTHROMYCIN AND NEOMYCIN. 